IRON CHELATION DECREASES HUMAN IMMUNODEFICIENCY VIRUS-1 TAT POTENTIATED TUMOR NECROSIS FACTOR-INDUCED NF-KAPPA-B ACTIVATION IN JURKAT CELLS

TNF-alpha stimulates HIV-1 replication via activation of the transcrip tion factor NF-kappa B. TNF-mediated activation of NF-kappa B is known to involve the intracellular formation of reactive oxygen intermediat es (ROIs). We recently demonstrated that HIV-1 Tat protein potentiates TNF-induced NF-kappa B activation by downregulation of manganese-depe ndent superoxide dismutase (MnSOD), shifting the cellular redox state towards pro-oxidative conditions. This study shows that treatment of J urkat cells with iron chelator deferoxamine (DFO) strongly decreases H IV-1 Tat-potentiated TNF-induced NF-kappa B activation but does not mo dify NF-kappa B activation by TNF-alpha. The ability of iron chelators to reduce Tat-potentiated TNF-induced NF-kappa B binding activity sug gests that iron and intracellular hydroxyl radicals (OH) are required for Tat effect. Moreover, we have shown that exogenously generated OH markedly enhanced TNF-induced NF-kappa B activation in a dose-dependen t manner while was not sufficient to trigger activation of NF-kappa B by itself. In addition, iron chelators had no effect either on MnSOD a ctivity or on the decrease of this activity by Tat. Iron chelators had also no effect on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSC), but could elevate the GSH:GSSC ratio decreased by Tat protein. These observations suggest that the formation of intracel lular OH - in the presence of iron ions play a major role in HIV-1 Tat enhancement of TNF-induced NF-kappa B activation and that iron chelat ion may protect Jurkat T cells, at least in part, against oxidative st ress induced by Tat.